Alzheimer's disease is a dementing neurodegenerative disease characterized by formation of senile plaques and neurofibrillary degeneration as well as degeneration of neurons. Senile plaques that are most characteristic of this disease are lesions composed mainly of amyloid-beta peptide (Aβ) derived from beta-amyloid precursor protein (βAPP) (Biochem Biopys Res Commun 122, 1131 (1984)), with apolipoprotein E (Brain Res 541, 163 (1984)) and a complement component C1q (Acta Neuropathol 57, 239 (1982)), etc being deposited. Aβ aggregates by itself, and formation of amyloid fiber is promoted by actions of non-Aβ amyloid components such as apolipoprotein E (Nature 372, 92 (1994)) and C1q (J Neurosci Res 46, 58 (1996)) as above described. Aβ consisting of 40-42 amino acids is secreted from various cells including neurons, and it is not toxic to cells at a normal concentration. However at a higher concentration, Aβ aggregates and becomes toxic to neurons (Science 250, 279 (1990)). In this process, it is known that several molecules such as RAGE (Nature 382, 685 (1996)) and scavenger receptor A (Nature 382, 716 (1996)) are present on the cell surface and act as receptors for aggregated Aβ. It seems that aggregation, accumulation, and toxicity to cells of amyloid are very important in neuronal degeneration process of Alzheimer's disease; therefore, inhibition of these processes will be an effective therapeutic method for Alzheimer's disease.
Accumulation of Aβ as amyloid is very characteristic of Alzheimer's disease, however it is being clarified that only accumulation of Aβ is not sufficient for toxicity to neurons as well as for the development of Alzheimer's disease (J. neurosci. 17, 7053 (1997)). On the other hand, as inferred from the fact that genetic polymorphism of proteins such as apolipoprotein E which promotes accumulation process of senile plaque amyloid serves as a risk factor for development of Alzheimer's disease (Science 261, 921 (1993)). It has been noted that unknown proteinaceous components in amyloid can greatly influence the accumulation and neuronal injury by amyloid; however the responsible components have not been identified yet.